Design and Solution‐Phase Synthesis of Membrane‐Targeting Lipopeptides with Selective Antibacterial Activity

Designing selective antibacterial molecules remains an unmet goal in the field of membrane‐targeting agents. Herein, we report the rational design and synthesis of a new class of lipopeptides, which possess highly selective bacterial killing over mammalian cells. The selective interaction with bacterial over mammalian membranes was established through various spectroscopic, as well as microscopic experiments, including biophysical studies with the model membranes. A detailed antibacterial structure–activity relationship was delineated after preparing a series of molecules consisting of the peptide moieties with varied sequence of amino acids, such as d‐phenylalanine, d‐leucine, and d‐lysine. Antibacterial activity was found to vary with the nature and positioning of hydrophobicity in the molecules, as well as number of positive charges. Optimized lipopeptide 9 did not show any hemolytic activity even at 1000 μg mL−1 and displayed >200‐fold and >100‐fold selectivity towards S. aureus and E. coli, respectively. More importantly, compound 9 was found to display good antibacterial activity (MIC 6.3–12.5 μg mL−1) against the five top most critical bacteria according to World Health Organization (WHO) priority pathogens list. Therefore, the results suggested that this new class of lipopeptides bear real promises for the development as future antibacterial agents. The rational design and synthesis of a new class of lipopeptides, which possess highly selective bacterial killing over mammalian cells, is reported. The selective interaction with bacterial over mammalian membranes was established through various spectroscopic, as well as microscopic experiments, including biophysical studies with the model membranes (see scheme).